WO2011124697A1 - Composés antimicrobiens à structure 1,4-naphtoquinone - Google Patents

Composés antimicrobiens à structure 1,4-naphtoquinone Download PDF

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WO2011124697A1
WO2011124697A1 PCT/EP2011/055537 EP2011055537W WO2011124697A1 WO 2011124697 A1 WO2011124697 A1 WO 2011124697A1 EP 2011055537 W EP2011055537 W EP 2011055537W WO 2011124697 A1 WO2011124697 A1 WO 2011124697A1
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group
chosen
compound
formula
aryl
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PCT/EP2011/055537
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Inventor
Yap Jean-Bertrand Boum Ii
Tamara Basta-Le Berre
Ursula Liebl
Hannu Myllykallio
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
Centre National De La Recherche Scientifique (C.N.R.S)
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Priority to EP11713770A priority Critical patent/EP2555764A1/fr
Priority to US13/640,187 priority patent/US20130102650A1/en
Publication of WO2011124697A1 publication Critical patent/WO2011124697A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/38—Quinones containing —CHO or non—quinoid keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Definitions

  • the present invention concerns new antimicrobial compounds having a 1 ,4-naphtoquinone structure.
  • Deoxythymidine 5'-monophosphate thymidylate or dTMP
  • dTMP an essential DNA precursor
  • dTMP precursors can be salvaged from the growth medium.
  • the last step of de novo thymidylate synthesis is the methylation of deoxyuridine 5'-monophosphate (uridylate or dUMP) to dTMP (J. S. Finer-Moore, D. V. Santi, R. M. Stroud, Biochemistry 42, 248 (Jan 21 , 2003).
  • This methylenetetrahydrofolate (CH 2 H 4 folate)-dependent methylation reaction is catalyzed by two distinct families of thymidylate synthases, ThyA (EC 2.1 .1 .45) and ThyX [EC 2.1 .1 .148, (also known as flavin dependent thymidylate synthase FDTS)], without detectable sequence or structural similarity (S. Graziani et al., J Biol Chem 281 , 24048 (Aug 18, 2006); Mathews, II et al., Structure 1 1 , 677 (Jun, 2003); A. G. Murzin, Science 297, 61 (Jul 5, 2002); and P.
  • ThyA EC 2.1 .1 .45
  • ThyX also known as flavin dependent thymidylate synthase FDTS
  • ThyX proteins have been proposed to transfer a hydride from the FADH2 co-factor directly to the uracil ring, in the absence of CH 2 H 4 folate.
  • both substrates, dUMP and CH 2 H 4 folate are required for oxidizing ThyX-bound FADH2, the direct proof for the role of dUMP as an initial electron sink is missing.
  • ThyX proteins are essential in many pathogenic bacteria (e.g. Helicobacter, Mycobacteria, Chlamydia and Rickettsia species as well as Bacillus anthracis), they provide a valuable anti-microbial target. There is a need in the art for the development of new antimicrobial compounds.
  • the aim of the present invention is to provide new antimicrobial compounds which inhibit specifically ThyX proteins.
  • the aim of the present invention is to provide new antimicrobial compounds which do not inhibit ThyA proteins.
  • the present invention relates to a compound having formula (I):
  • - Ri is chosen from the group consisting of:
  • R'i being chosen from the group consisting of: H , -OH , halogen, alkyl, aryl, -CHO, -CN , -N0 2 , -S R a , -OR a , - N R a R p , -CON RcRp, -COORa, and -N HCOR a , R a and R p representing independently from each other H , an alkyl group or an aryl group, R'i being preferably in para position, and
  • R' representing an aryl or heteroaryl group, said aryl and heteroaryl groups being possibly substituted
  • - R 2 is chosen from the group consisting of: -OH and halogen
  • R 3 , R 4 , R5 and R 6 are chosen, independently from each other, in the group consisting of: H , -OH , halogen, alkyl, -CHO, -CN , -N0 2 , -S R a , -OR a , - N R a R p , -CON RcRp, -COORa, and -N HCOR Q , R Q and R p being as defined above;
  • a particular group of com ounds are of formula ( ⁇ ):
  • - Ri is chosen from the group consisting of: H, cycloalkyl, aryl, -CH 2 -aryl, and -CH 2 -CO-R' groups, R' representing an aryl or heteroaryl group, said cycloalkyl, aryl and heteroaryl groups being possibly substituted,
  • - R 2 is chosen from the group consisting of: -OH and halogen
  • R 3 , R 4 , R5 and R 6 are chosen, independently from each other, in the group consisting of: H, -OH, halogen, alkyl, -CHO, -CN, -N0 2 , -SR a , OR a , -NR a R p , -CONR a Rp, -COOR a , and -NHCOR Q , R Q and R p representing independently from each other H, an alkyl group or an aryl group.
  • aryl refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution may be substituted by a substituent.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • aryl refers to a group comprising from 6 to 30, preferably from 6 to 20, and for example from 6 to 10 carbon atoms.
  • radical -C 6 H 4 - refers to a divalent phenylene radical.
  • the phenylene ring of radical -C 6 H 4 - can be either substituted in ortho, meta or para position, and can be represented by the formula:
  • preferred aryl groups are phenyl and substituted phenyl.
  • heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 1 1 -14 membered tricyclic ring system having 1 -3 heteroatoms if monocyclic, 1 -6 heteroatoms if bicyclic, or 1 -9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1 -3, 1 -6, or 1 -9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein any ring atom capable of substitution may be substituted by a substituent.
  • preferred heteroaryl groups are aromatic monocyclic compounds comprising 5 or 6 atoms, and most preferably comprising 5 atoms.
  • said 5 or 6 membered rings comprise 1 or 2 heteroatoms selected from O, N, or S.
  • cycloalkyi as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution may be substituted by a substituent.
  • cycloalkyi moieties include, but are not limited to, cyclohexyl and adamantyl.
  • preferred cycloalkyi groups are cyclohexyl groups, and substituted cyclohexyl groups.
  • substituted refers to a group "substituted” on an aryl, heteroaryl or cycloalkyi group at any atom of that group.
  • Suitable substituents include, without limitation, alkyl, alkenyl, alkynyl, aryl, alkoxy, halo, hydroxy, cyano, nitro, amino, -SO 3 H, sulphate, phosphate, perfluoroalkyl, perfluoroalkoxy, methylenedioxy, ethylenedioxy, carboxyl, oxo, thioxo, imino (alkyl, aryl, aralkyl), -S(0) n alkyl (where n is 0-2), -S(0) n aryl (where n is 0-2), -S(0) n heteroaryl (where n is 0-2), -S(0) n heterocyclyl (where n is 0- 2), amine (mono-, di-
  • aryl or heteroaryl groups are alkyl, amino, amine, hydroxy, alkoxy, halo, perfluoroalkyl such as -CF 3 , heterocyclyl, amide, and ester.
  • cycloalkyi in particular cyclohexyl, groups are aryl groups, and most preferably substituted aryl groups. Most preferred substituents on cyclohexyl groups are aryl groups substituted by at least one halogen atom, and preferably by chlorine atom in para position.
  • alkyl means a saturated or unsaturated aliphatic hydrocarbon group which may be straight or branched having about 1 to about 12 carbon atoms in the chain. Preferred alkyl groups have 1 to about 6 carbon atoms in the chain.
  • Branched means that one or lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
  • «Lower alkyl» means about 1 to about 4 carbon atoms in the chain which may be straight or branched.
  • the alkyl may be substituted with one or more «alkyl group substituants», which may be the same or different, and include for instance halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy.
  • arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group (possibly substituted).
  • arylalkyl or “aralkyl” include benzyl and 9-fluorenyl groups.
  • alkoxy refers to an -O-alkyl radical.
  • halo refers to the atoms of the group 17 of the periodic table (halogens) and includes in particular fluorine, chlorine, bromine, and iodine atom.
  • heterocyclyl refers to a nonaromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 1 1 -14 membered tricyclic ring system having 1 -3 heteroatoms if monocyclic, 1 -6 heteroatoms if bicyclic, or 1 -9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1 -3, 1 -6, or 1 -9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein any ring atom capable of substitution may be substituted by a substituent.
  • oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
  • alkenyl as employed herein includes partially unsaturated, nonaromatic, hydrocarbon groups having 2 to 12 carbons, preferably 2 to 6 carbons.
  • alkynyl as employed herein includes unsaturated, nonaromatic, hydrocarbon groups having 2 to 12 carbons, preferably 2 to 6 carbons, and comprising at least one triple bond.
  • acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.
  • R a , R b , R c , R d , R e , R g , R h and R being chosen, independently from each other, in the group consisting of the following substituents:
  • halogen such as I, Br, CI or F
  • alkyi group said alkyi group being possibly substituted in particular by one or more substituents chosen in the group consisting of the following substituents: halogen, alkenyl or alkynyl groups, aryl groups, -COR Q , -COOR Q , -SR Q , -OR Q or -NR a Rp groups, R Q and R p being as defined above,
  • the compounds herein described may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well-known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a compound are intended, unless the stereochemistry or the isomeric form is specifically indicated.
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are not biologically or otherwise undesirable.
  • the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • non-toxic pharmaceutically acceptable salts refers to non-toxic salts formed with nontoxic, pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, fumaric, methanesulfonic, and toluenesulfonic acid and the like.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • compositions both for veterinary and for human use, useful according to the present invention comprise at least one compound having formula (I) as above defined, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
  • active ingredients necessary in combination therapy may be combined in a single pharmaceutical composition for simultaneous administration.
  • compositions, carriers, diluents and reagents are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
  • compositions that contains active ingredients dissolved or dispersed therein are well understood in the art and need not be limited based on formulation.
  • compositions are prepared as injectables either as liquid solutions or suspensions; however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared.
  • the preparation can also be emulsified.
  • the pharmaceutical compositions may be formulated in solid dosage form, for example capsules, tablets, pills, powders, dragees or granules.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • compositions can be administered in a suitable formulation to humans and animals by topical or systemic administration, including oral, rectal, nasal, buccal, ocular, sublingual, transdermal, rectal, topical, vaginal, parenteral (including subcutaneous, intra-arterial, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Total daily dose of the compounds of the invention administered to a subject in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
  • a particular group of compounds of the present invention consists of compounds of formula (I) wherein R 2 is halogen, in particular Br.
  • Such compounds may be represented by the below formula (1-1 ):
  • Hal representing a halogen atom, in particular Br.
  • R 4 , R 5 and R 6 are H.
  • a particular group of compounds of formula ( ⁇ ) consists of compounds of formula ( ⁇ ) wherein is H and R 2 is halogen, in particular Br.
  • Hal representing a halogen atom in particular Br.
  • R 4 , R 5 and R 6 are H.
  • Another particular group of compounds of the present invention consists of compounds of formula (1-1 ) wherein R 4 , R 5 and R 6 are H and Hal is Br.
  • R 3 is chosen in the group consisting of: H , -OH , halogen, alkyl, -CHO, -CN, -N0 2 , -SR Q , -OR q , -NR a Rp, -CONR a R p , -COOR A , and -NHCOR Q , R Q and R p representing independently from each other H , an alkyl group or an aryl group.
  • R 3 is -OH .
  • Another particular group of compounds of the present invention consists of compounds of formula (I) wherein R 2 is -OH .
  • Such compounds may b
  • R 3 is -OH.
  • R 3 is chosen in the group consisting of: H , -OH , halogen, alkyl, -CHO, -CN, -N0 2 , -SR Q , -OR Q , -NR a Rp, -CONR A R P , -COOR A , and -NHCOR Q , R Q and R P representing independently from each other H , an alkyl group or an aryl group.
  • R 3 is -OH .
  • a particular group of compounds of the present invention consists of compounds of formula (I) wherein R 3 is -OH and R 4 , R 5 and R 6 are H.
  • a particular group of compounds of formula ( ⁇ ) consists of compounds of formula (I) wherein R 3 , R 4 , R 5 and R 6 are H, R 2 is -OH, and Ri is a cycloalkyl group, preferably a substituted cyclohexyl group.
  • a preferred compound of this group is atovaquone (CAS RN 95233-18-4) and has the following formula:
  • a group of compounds of the present invention consists of compounds of formula (I) wherein R 3 , R 4 , R 5 and R 6 are H, and R 2 is -OH.
  • the present invention relates to compounds having formula (II):
  • Ri is as defined above in formula (I), for their use for the prevention and/or the treatment of bacterial infections.
  • compounds of formula ( ⁇ ) are of formula (II'):
  • R-i is chosen from the group consisting of: aryl, -CH 2 -aryl, and -CH 2 -CO-R' groups, R' being as defined above in formula ( ⁇ ), for their use for the prevention and/or the treatment of bacterial infections.
  • the present invention relates to compounds having formula (II) wherein Ri is a phenyl group, possibly substituted, for their use for the prevention and/or the treatment of bacterial infections.
  • Ri is a substituted phenyl group, it may comprise one or several substituents, and in particular one or two substituents.
  • Ri is a substituted phenyl group
  • the substituents are chosen from the group consisting of: -CHO, -CN, aryl, alkyl, halo, nitro, hydroxy, -SR Q , -OR Q , -NR Q R P , -CONR c Rp, -COOR c , and -NHCOR Q , R Q and R p being as defined above.
  • Ri is a phenyl group with one substituent in para position.
  • Ri is a phenyl group, substituted by an aryl group, and preferably a phenyl group.
  • Ri is chosen from the group consisting of: -CH 2 -aryl and -CH 2 -CO-R' groups, R' being as defined above.
  • Ri is a -CH 2 -aryl group
  • said aryl group is a phenyl group or a substituted phenyl group.
  • said aryl group is a substituted phenyl group, it may comprise one or several substituents, and in particular one or two substituents.
  • Ri is chosen from the group consisting of: -CH 2 -C 6 H 4 -R'i group and -CH 2 -CO-R' group, R'i and R' being as defined above.
  • Ri is chosen from the group consisting of: -CH 2 -C 6 H 4 -R'i group and -CH 2 -CO-R' group, R'i and R' being as defined above.
  • the present invention thus also relates to compounds for the use as defined above, having formula (I) wherein is chosen from the groups having the following formula (A):
  • R'i being as defined above.
  • the phenyl group may comprise several substituents, that is to say it may comprise several R'i groups being identical or different.
  • R'i is a group in para position having formula -OR' 2 , R' 2 being H or an alkyl group comprising from 1 to 6 carbon atoms, and preferably from 1 to 3 carbon atoms.
  • R'i is a para-methoxy group.
  • Another group of compounds of the invention is constituted by compounds having formula (II) wherein Ri is chosen from the groups having formula -CH 2 -CO-R', R' being as defined above.
  • Another group of compounds of the invention is constituted by compounds having formula (I) wherein is chosen from the groups having formula -CH 2 -CO-R', R' being as defined above.
  • R' is chosen from the aryl groups, possibly substituted.
  • R' is a phenyl group, possibly substituted.
  • Ri is a substituted phenyl or aryl group, it may comprise one or several substituents, and in particular one or two substituents.
  • Ri is a substituted phenyl or aryl group
  • the substituents are chosen from the group consisting of: H, -OH, halogen, alkyl, aryl, -CHO, -CN, -N0 2 , -SR Q , -OR c , -NR a Rp, -CONR c Rp, -COOR a , and -NHCOR a , R a and R p being as defined above.
  • R' is a phenyl group with one substituent in para position.
  • the present invention thus also relates to compounds for the use as defined above, having formula (II) whe
  • R' 3 being chosen from substituents chosen from the group consisting of: H, -OH, halogen, alkyl, aryl, -CHO, -CN, -N0 2 , -SR Q , -OR Q , -NR a R p , -CONR a R p , -COOR a , and -NHCOR Q , R Q and R p being as defined above, and R' 3 being preferably in para position.
  • the present invention thus also relates to compounds for the use as defined above, having formula (I) wherein is chosen from the groups having formula (B):
  • R' 3 being chosen from substituents chosen from the group consisting of: H, -OH, halogen, alkyl, aryl, -CHO, -CN, -N0 2 , -SR a , -OR a , -NR a R p , -CONR a R p , -COORc, and -NHCOR Q , R a and Rp being as defined above, and R' 3 being preferably in para position.
  • the phenyl group may comprise several substituents, that is to say it may comprise several R' 3 groups being identical or different.
  • R' 3 is a group in para position chosen from the alkyl groups comprising from 1 to 6 carbon atoms, and preferably from 1 to 3 carbon atoms, and the groups having formula -OR' 4 , R' 4 being H or an alkyl group comprising from 1 to 6 carbon atoms, and preferably from 1 to 3 carbon atoms.
  • R' 3 is a para-methoxy group or a para-methyl group.
  • Another group of compounds of the invention is constituted by compounds having formula (II) wherein R ⁇ is chosen from the groups having formula -CH 2 -CO-R', R' being chosen from the heteroaryl groups, possibly substituted.
  • Another group of compounds of the invention is constituted by compounds having formula (I) wherein R ⁇ is chosen from the groups having formula -CH 2 -CO-R', R' being chosen from the heteroaryl groups, possibly substituted.
  • the present invention thus also relates to compounds for the use as defined above, having formula (II) wherei
  • R' 5 being chosen from H
  • the present invention thus also relates to compounds for the use as defined above, having formula (I) wherein R ⁇ is chosen from the groups having formula (C):
  • R' 5 being chosen from H
  • the phenyl group may comprise several substituents, that is to say it may comprise several R' 5 groups being identical or different.
  • the most preferred compounds of the invention are the following compounds:
  • the present invention relates to the compounds as defined above for their use for the prevention and/or the treatment of bacterial infections chosen from Mycobacterium or Helicobacter species bacteria infections, and preferably from Mycobacterium smegmatis and Helicobacter pylori infections.
  • the present invention relates to the compounds as defined above for their use for the prevention and/or the treatment of bacterial infections, due to bacteria expressing ThyX protein.
  • ThyX protein Among bacteria expressing ThyX protein, one may cite Borrelia burgdorferi, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Corynebacterium diphteriae, Helicobacter pylori, Leptospira interrogans, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis, Rickettsia prowazeki, Rickettsia rickettsii, and Treponema pallidum.
  • the present invention relates to compounds having formula (I) as defined above for their use for the prevention and/or the treatment of bacterial infections by inhibition of ThyX protein.
  • the compounds of formula (I) of the present invention are specific ThyX inhibitors and they are compounds known from the skilled person.
  • above compounds (1 ), (2), (3), (4), (5) and (6) have the following CAS RN 67287- 16-5, 59304-99-3, 59382-19-3, 412966-59-7, 413571 -44-5, and 722461 -1 1 -2, respectively.
  • Figure 1 represents dose-response curves for compounds of the invention showing the fractional velocity of the reaction as function of inhibitor concentration are shown.
  • IC 50 values were derived by fitting the data to sigmoidal dose-response equation.
  • Figure 2 represents the initial velocity of NADPH oxidation as a function of dUMP concentration in absence or presence of atovaquone. Atovaquone concentrations in the assays are indicated on the right.
  • Figure 3 represents the Lineweaver-Burk plot in absence or presence of atovaquone. Atovaquone concentrations in the assays are indicated on the right.
  • NADPH oxidation assay for PBCV-1 ThyX activity (Graziani, S., Xia, Y., Gurnon, J. R., Van Etten, J. L, Leduc, D., Skouloubris, S., Myllykallio, H., and Liebl, U. (2004) Functional analysis of FAD-dependent thymidylate synthase ThyX from Paramecium bursaria Chlorella virus-1 . J. Biol. Chem. 279, 54340-54347) was adapted for a medium throughput inhibitor screen (MTS) in 96-well plates.
  • MTS medium throughput inhibitor screen
  • a typical assay with a final volume of 200 ⁇ contained 200 ⁇ NADPH, 2 ⁇ CH2H4folate, 5 ⁇ dUMP, 1 mM MgCI2, 1 % glycerol, 62.5 ⁇ FAD and 400 nM PBCV-1 ThyX.
  • 1982 compounds from the National Cancer Institute diversity set I and 340 natural compounds, selected for their diversity and drug-likeness (GreenPharma) (all in DMSO) were added to a final concentration of 20 ⁇ for the initial screen.
  • the microplates were prepared by a liquid handling robotic workstation (Xiril X75), and manually transferred to the automated microplate reader Chameleon II (Hidex).
  • H. pylori ThyX was determined using a tritium release assay that measures deprotonation at the 5-position of the pyrimidine ring of dUMP substrate and detects the formation of tritiated water during the ThyX reaction (Leduc, D., Graziani, S., Lipowski, G., Marchand, C, Le Marechal, P., Liebl, U., and Myllykallio, H. (2004) Proc. Natl. Acad. Sci. U. S. A. 101 , 7252-7257).
  • This assay was adapted for automatization to a 96-well plate format.
  • a typical reaction mix contained 50 mM HEPES pH 7.5, 1 mM MgCI 2 , 10 % glycerol, 62.5 ⁇ FAD, 2.5 ⁇ dUMP, 200 ⁇ NADPH, 200 ⁇ CH 2 H 4 folate (Merck Eprova) and 400 nM of ThyX in a in final volume of 25 ⁇ _.
  • the specific activity of the [5-H 3 ]dUMP stock (Moravek) used was 13,6 Ci/mmol.
  • the reactions were started by adding the enzyme, and the assay mixtures were incubated for 15 minutes at 37 ⁇ C.
  • the reaction was then stopped by addition of 175 ⁇ _ of 10 % (wt/vol) activated Norit A charcoal (Sigma) in 2% trichloroacetic acid to remove radioactive nucleotides from the reaction mixture. Released tritium was separated from the reaction substrates using vacuum manifold and Unifilter 350 GF/C plates (Whatman) during 15 minutes at -20 mm Hg. The radioactivity remaining in the filtrate was measured by adding Ecolune (ICN) scintillation liquid and counted with the Chameleon II microtiterplate reader. All reactions were done in triplicate and included controls without compounds, without enzyme and with DMSO only.
  • ICN Ecolune
  • ThyA The effect of the primary hits on the activity of human ThyA was determined by following the increase in absorbance at 340 nm that accompanies the conversion of CH 2 H 4 folate into H 2 folate during the ThyA catalyzed reaction (Meek TD, Garvey EP, Santi DV. Purification and characterization of the bifunctional thymidylate synthetase-dihydrofolate reductase from methotrexate-resistant Leishmania tropica. Biochemistry. 1985 Jan 29;24(3):678-86).
  • 160 1 ,4-naphtoquinone (1 ,4 NQ) derivatives were purchased from Chembridge Corporation along with a control library that consisted of 80 1 ,2 NQ derivatives. Isis and Chime (MDL) were used to select for molecules with the following criteria: molecular weight between 160 and 480 Da, number of Hdonors less than 5 and number of H-acceptors less than 10, calculated XlogP value between 0 and 5.6, total polar surface area less than 150 A 2 and number of rotative bonds between 2 and 10.
  • MDL Isis and Chime
  • ThyX inhibitors To increase robustness and specificity of ThyX inhibitors, additional assays have been performed. First, the effects of fourteen ThyX inhibitors have been tested using NADPH oxidation assays or by following the loss of tritium from [5- 3 H]dUMP in a microtiter plate-4 compatible format. The use of two individual assays that measure the early and late reaction steps of ThyX catalysis excluded the possibility that the results obtained using the colorimetric assay were affected by the absorption properties of the screened molecules. These tests on ThyX proteins have been performed from Helicobacter pylori, Chlamydia trachomatis, and Mycobacterium tuberculosis, and used human thymidylate synthase ThyA as the negative control. These tests identified a single compound that drastically decreased ThyX activity in the two independent enzymatic assays, but did not influence the activity of human thymidylate synthase ThyA
  • the identified compound, 2-bromo-8-hydroxy-1 ,4-naphthoquinone (compound 2E04) was originally isolated from the fruit of malaysian persimmon (Diospyros maritima), and is related to the lipid-soluble vitamin K1 [phylloquinone (also of plant origin)] that is required for efficient blood coagulation.
  • Table 1 Hits issued from the screen of the library of 160 1 ,4-naphthoquinone derivatives. Percentage of inhibition using deprotonation assays in the presence of 20 ⁇ compounds is indicated.
  • a typical assay (200 ⁇ _) contained 200 ⁇ NADPH, 2 ⁇ dUMP, 1 mM MgCI 2 , 1 % glycerol, 10 ⁇ FAD, 200 nM of PBCV-1 ThyX and different concentrations of inhibitors ranging from 0.1 ⁇ to 40 ⁇ .
  • the reactions were started by injection of NADPH and the absorbance at 340 nm was followed for 3 min at 37 ⁇ ⁇ . DMSO and no enzyme were used as high and no activity controls.
  • a molar extinction coefficient for NADPH oxidation at 340 nm of 6220 M " cm "1 was used for quantification of absorption changes.
  • the optical path length was 0.5 cm.
  • the obtained V V 0 values were plotted for each inhibitor concentration and fitted to sigmoidal dose-response curves using GraphPad Prism 4 Software.
  • Helicobacter pylori strain 26695 and SS1 were grown on either blood agar base two (Oxoid) plates supplemented with 10% defibrinated horse blood (Oxoid) or in liquid culture in brain-heart infusion broth (Oxoid) supplemented with 10% FBS (Gibco BRL).
  • An antibiotics- fungicide mix consisting of vancomycin (final concentration 10 g/ml), polymyxin B (2.5 units per liter), trimethoprim (5 g/ml), and fungizone (2.5 g ml) was added. Plates were incubated at 37 °C under microaerobic atmosphere in jars using the CampyGen gas generating system (Oxoid). Liquid cultures were shaken at 175 rpm.
  • Mycobacterium smegmatis strain mc2 155 was grown on either LB agar plates or in liquid culture in LB medium supplemented with 0.2 % glycerol and 0.05 % Tween 80 (Sigma). Liquid cultures were shaken at 175 rpm.
  • E. coli MG1655 and E. coli FE10 AthyA::thyX were grown in LB medium overnight. The cells were then harvested and washed two times with M9 medium to remove the remaining thymidine. The cells were diluted to OD600 of approximately 0.1 in M9 medium or M9 medium supplemented with 40 ⁇ g/ml of thymidine. 1 ml cells suspension was transferred to 24 well microplates (Nunc) and 10 ⁇ of 2E04 was then added to a final concentration of 60 ⁇ to half of the wells. No cells and DMSO-only controls were included for each medium composition.
  • the plates were closed with appropriate plastic lids and incubated at 37 ⁇ ⁇ with shaking at 160 rpm. After 24 h of incubation, 100 ⁇ of 10 fold serial dilutions were plated onto LB plates or LB plates supplemented with kanamycin (40 ⁇ g ml). Colonies were enumerated after overnight incubation at 37°. Colony forming units (CFU) per milliliter for each growth condition were determined from three independent experiments.
  • CFU Colony forming units
  • MICs Minimal inhibitory concentrations were determined using a broth microdilution test in 24 well microtiter plates. For test inoculums an overnight preculture of H. pylori strain 26695 was diluted to OD600 of approximately 0.1 and 1 ml of this suspension was transferred to each well. 10 ⁇ of two-fold serial dilutions of each compound in DMSO were added and the covered plates were incubated for 24 h at 37 ⁇ ⁇ with orbital shaking at 150 rpm under microaerophilic conditions obtained using CampyGen gas generating system (Oxoid). The MIC was determined as the lowest compound concentration resulting in complete growth inhibition after 24 h of incubation.
  • the diameters of each inhibition zone were measured (disk surface and a DMSO inhibition zone were subtracted). All experiments were done in triplicate, including a DMSO-only control on each plate. MIC determination by broth microdilution was not possible for M. smegmatis mc2 1 55 due to build up of cell aggregates in liquid cultures. The susceptibility of M. smegmatis mc2 1 55 towards selected compounds was thus tested using disc diffusion test on LB-agar plates as described above. The inhibition diameters were read after 48h of incubation at 37 ⁇ C.
  • the molecule C8-C1 was an obvious choice for more detailed mechanistic and structural studies as we found it to be non-genotoxic and to exhibit low cytotoxic activity, which was further decreased in metabolic activation tests using cultured human lymphoblastoid TK6 cells (P. W. Hastwell et ai, Mutagenesis 24, 455 (Sep, 2009)).
  • Genotoxicity and cytotoxicity of 2E04 and 5 compounds issued from the screen of the dedicated library of 160 1 ,4-NQs were determined using the GreenScreen HC genotoxicity screening assay without metabolic activation.
  • Two strains of cultured human lymphoblastoid TK6 cells were used, the test strain (GenM-T01 ) and the non-fluorescent control strain (GenM-C01 ), the latter was used to allow correction for any autofluorescence from the test.
  • the plates were analyzed at 24 hour and 48 hour time points using a microplate reader, that allows measurements of light absorbance and fluorescence for cells and solutions in the microplate wells.
  • Absorbance is proportional to cell proliferation, which is lowered by toxic analytes
  • fluorescence is proportional to the activity of the cell's DNA repair system, which is increased by genotoxic analytes.
  • compound C8-C1 was selected for further testing using GreenScreen HC with metabolic activation using the S9 fraction.
  • the GreenScreen HC +S9 protocol uses the same cultured TK6 cell strains (GenM-C01 and GenMTOI ). 10 Mg/ml of compound C8-C1 was incubated with both cell strains in the presence of 1 % v/v S9 fraction mix in Exposure Medium at 37°C (5 % C0 2 , 95 % humidity) for 3 hours. After a recovery period of 45 hours the GFP fluorescence signal and cell viability (assessed by propidium iodide uptake) were measured.

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Abstract

La présente invention porte sur un composé répondant à la formule (I) dans laquelle : R1 est choisi dans le groupe constitué par : le groupe phényle, éventuellement substitué, le groupe -CH2-C6H4-R'1, R'1 étant choisi dans le groupe constitué par : H, -OH, halogène, alkyle, aryle, CHO, -CN, -NO2, -SRá, -ORá, -NRáRâ, -CONRáRâ, -COORá et -NHCORá, Rá et Râ représentant chacun indépendamment de l'autre H, un groupe alkyle ou un groupe aryle, R'1 étant de préférence en position para, et un groupe -CH2-CO-R', R' représentant un groupe aryle ou hétéroaryle, lesdits groupes aryle et hétéroaryle étant éventuellement substitués, R2 est choisi dans le groupe constitué par : -OH et un halogène et R3, R4, R5 et R6 sont chacun en particulier H, destiné à être utilisé pour la prévention et/ou le traitement d'infections bactériennes.
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